1. Field of the Invention
The present invention generally relates to non-effervescent, solid dosage forms adapted for oral administration of 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazol-4-one (ondansetron) as an anti-emetic active ingredient for the prevention of nausea and vomiting. Particularly, the invention relates to solid dosage forms containing ondansetron in the form of orally disintegrating tablets.
2. Background Art
U.S. Pat. No. 4,695,578 discloses that ondansetron is a highly selective and potent antagonist of 5-hydroxytryptamine (5-HT) at 5HT3 receptors in the gastrointestinal tract, where it blocks both sites of serotonin-induced nausea and vomiting (emesis). Emesis is a frequent side effect of cancer chemotherapeutic agents, such as cisplatin. Emesis causes serious problems in cancer chemotherapy, and in some patients emesis is so severe that therapy must be discontinued. Anti-emetic agents are therefore often administered in order to alleviate this side effect of cancer chemotherapy. Ondansetron, together with its physiologically acceptable salts is used in the treatment of a variety of conditions ameliorated by administration of 5HT3 receptor antagonists, such as emesis, including the nausea and vomiting induced by cancer chemotherapy and radiotherapy.
Consequently, ondansetron can produce a significant reduction, or a complete inhibition of nausea and vomiting in patients treated with cancer chemotherapeutics of moderate- or high-emetic potential. Similarly, the compound prevents radiation-induced nausea and emesis.
Administration of oral or injectable free base and salts of ondansetron, e.g., hydrochloride dihydrate, is disclosed in U.S. Pat. Nos. 4,753,789; 4,929,632; 5,955,488 and 6,063,802.
Oral administration in the form of a conventional tablet, pill or capsule constitutes a generally preferred route for administration of pharmaceuticals since this route is generally convenient and acceptable to patients. Unfortunately, such compositions may be associated with certain disadvantages, particularly in the treatment of pediatric or geriatric patients, who may dislike or have difficulty in swallowing such compositions, or where administration of a conventional tablet, pill or capsule is not feasible. It is highly desirable, particularly in the treatment of acute conditions, that pharmaceutical compositions have a rapid and consistent onset of action combined with sustained activity and good bioavailability. Rapid absorption can be achieved by parenteral injection but this is unacceptable to many patients, particularly if the drug is to be self-administered without direct medical supervision.
Preparations for oral administration normally come in the form of a tablet, granule, powder or solution. However, since a solid preparation need be swallowed with some water, the elderly, infants and patients who have difficulty in swallowing prefer dosage forms such as a liquid preparation or a rapidly disintegrating tablet which easily disintegrates by the action of saliva.
Although certain liquid dosage forms may be suitable for the elderly, infants or patients who have difficulty in swallowing, they have shortcomings such as difficulty in handling, especially in measuring an accurate dosage, and in that they are not suitable for drugs which are unstable in a moist environment.
Orally disintegrating solid dosage forms have significant advantages over other dosage forms, particularly for patients who cannot, or will not, swallow a tablet or capsule. Moreover, solid dosage forms are far more convenient than liquids. Formulations such as porous tablets, chewable tablets, non-chewable tablets, freeze-dried dosage forms and dosage forms containing microparticles and effervescent couples are disclosed in U.S. Pat. Nos. 3,885,026, 4,134,943, 5,225,197, 5,178,878, 5,955,488, and 6,024,981. Some of the dosage forms disclosed in the listed patents are suitable for some patients, however, the dosage forms pose significant problems in terms of production, storage, transport and during consumer usage. The dosage forms are also significantly more costly to produce, e.g., freeze-drying processes are expensive and time-consuming. In addition, the effectiveness of a freeze-drying process depends on the physico-chemical parameters of the active substances used. For certain active substances, especially those having a high solubility in water, it is difficult or impossible to apply a freeze-drying process. Finally, the development of units with high doses (up to 500 mg or even 1000 mg) of active ingredients and/or combinations of active ingredients is difficult with freeze-drying.
In addition, freeze-dried tablets are so fragile that the matrix material must be formed by freeze-drying in an individual tablet-sized container. While the use of an effervescent couple in combination with microparticles may overcome the need for such extreme measures, the need to minimize in-mouth disintegration times still requires the use of non-traditional packaging and processing methodology. For example, normal conveyors such as vibratory conveyors or bulk hoppers common in the pharmaceutical industry could not be used, as these high-speed, high-volume devices tend to cause damage to the resulting tablets. Similarly, the resulting tablets cannot be stored on a hopper after tableting but before packaging. They can not be packaged in a conventional, multi-tablet bottle, individual foil pouches or traditional blister packaging due to high likelihood of tablet breakage. This can seriously interfere with the processing efficiencies of high-volume presses.
There exists a need in the art for alternatives to expensive manufacturing processes, e.g., freeze drying, to produce orally disintegrating ondansetron tablets, which are bioequivalent to the existing Zofran orally disintegrating tablets.